There is a critical need for alternative therapeutic strategies applicable to early aortic valve disease (AVD) that prevent disease progression. Diseased valves are characterized by cell-matrix abnormalities including elastic fiber fragmentation (EFF) and aberrant angiogenesis remodeling. The long-term goal is to develop pharmacologic means to treat and prevent AVD. Recently, we identified aberrant angiogenesis as an early disease process in human AVD preceding inflammation, and identified the emilin-1 deficient (Emi1-/-) mouse as a unique model of latent AVD, characterized by aortic valves with EFF, fibrosis and aberrant angiogenesis, similar to human AVD. The objectives for this study are to determine the impact of EFF on AVD progression, delineate the mechanisms by which angiogenesis causes early-onset AVD, and assess the efficacy of elastic and/or Erk1/2 inhibition in a mouse model of AVD. These objectives align directly with NHLBI recommendations regarding specific AVD research priorities, and are consistent with the overarching goals of the NIH. The central hypothesis is that elastic-mediated EFF is a critical intermediate that activates VEGF- ERK1/2 signaling and results in progressive but reversible aberrant angiogenesis in AVD. This novel concept is supported by preliminary data and challenges current clinical and research paradigms. The rationale for the proposed research is that a better mechanistic understanding of early AVD pathogenesis and disease progression will result in new targeted therapies that prevent the development of advanced disease and preclude the need for surgery. Based on strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1) Determine the relationship between EFF, inflammation and AVD progression in mouse; 2) Determine if ERK1/2-mediated VEGF signaling is necessary and/or sufficient to cause aberrant angiogenesis in mouse and human AVD; and 3) Determine if the progression of AVD can be prevented or reversed by inhibiting elastase and/or p-Erk1/2 activity. The contribution of the proposed research is expected to be the identification of a mechanistic role for EFF in early AVD pathogenesis through activation of VEGF- ERK signaling and aberrant angiogenesis. These studies are significant because they will directly improve our understanding of early AVD pathogenesis and disease progression. The central concept is that EFF is a critical aspect of AVD pathogenesis regardless of etiology; therefore, it is imperative to study downstream effects in order to design new therapies. The central concept is that EFF plays a central role in AVD progression independent of atherosclerosis and age-related inflammation. The proposed research is innovative because it identifies a new intellectual basis for approaching early therapeutic windows in AVD. The expected outcomes will be defining the impact of EFF dosage on AVD progression, identifying early AVD mechanisms that regulate angiogenesis, and determining the preclinical utility of elastase and/or p-Erk inhibition to prevent and/or treat AVD. These translational studies will improve our understanding of early valve disease pathogenesis, and more generally pre-inflammatory processes, and provide the basis for identifying novel and important therapeutic approaches.